JP2521739B2 - Liver disease treatment agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of formula (I) The present invention relates to a therapeutic agent for liver diseases, which comprises a 1,3-benzodioxole derivative represented by

The present inventors have previously found that alkyl-substituted-1,3-benzodioxole has an excellent therapeutic effect on liver diseases, and applied for a patent for this (Japanese Patent Application No. 60-168422). The present invention has been completed as a result of further development of research on this therapeutic agent for liver diseases.

Most of the compounds represented by the above formula (I) are already known compounds. However, so far, the use of the present compound (I), particularly the use as a medicine, has not been known at all.
As a result of intensive studies on the pharmacological action of the present compound (I), the present inventors have found that it has a hepatic disorder inhibitory action, and completed the present invention. That is, the present invention has the formula (I) [In the formula, X is independently a lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, an amino group, a lower alkylamino group, a di (lower alkyl) amino group, a lower alkanoylamino group, (N-lower alkyl-N- A lower alkanoyl) amino group, a lower alkylsulfonylamino group, or a ureido group, or two X's may be combined to form a methylenedioxy group, and Y is independently a lower alkyl group. Where n is an integer of 1 to 4 and n ′ is an integer of 0 to 3. However, the total sum of n and n'do not exceed 4.] The present invention provides a therapeutic agent for liver diseases containing a 1,3-benzodioxole derivative as an essential component.

The compound represented by the formula (I) can be produced, for example, according to the synthetic route shown below.

In each of the above synthetic routes, R and R'represent a lower alkyl group, X represents a halogen atom, and the symbols a to t have the following meanings.

To prepare the compound of formula (I) according to this synthetic route, known methods [for example, Tetrahedron Letters, 23, 949-952 (1982) and Liebig Annalen del Chemie ( Liebigs An
nalen der Chemie), 1975, pp. 611-616], and 1,3-benzodioxole having a phenolic hydroxyl group or amino group, which can be easily synthesized and is easily available as a commercial product. A derivative is used as a starting material, and this is reacted with a reagent such as an alkyl halide, an acid anhydride, or an alkylsulfonyl chloride, or a Friedel derivative of a 1,3-benzodioxole derivative with an acid chloride or an acid anhydride.・ Perform craft reaction, etc.

 Representative examples of the compound represented by the formula (I) are shown below.

In order to use the compound represented by the formula (I) as a therapeutic agent for liver diseases, the compound may be used alone or in accordance with a customary method using a pharmaceutically acceptable excipient, diluent or adjuvant to prepare a powder or granule. , Tablets, capsules, injections, etc. are prepared and applied orally or parenterally by a usual method.
The dose of the compound of formula (I) varies depending on the age, sex, body weight, symptom of the patient, etc.
An advantageous range is from 0.1 to 50 mg / kg / day, preferably from 1 to 10 mg / kg, and when administered parenterally, from 0.05 to 25 mg / kg body weight / day, preferably from 0.5 to 5 mg. The administration is preferable because the daily dose is divided into several doses. Depending on the symptoms, it may be necessary to administer more than the upper limit of the dose, but the acute toxicity value (50% lethal dose) of the compound of formula (I) in mice is 500 mg / Kg by oral administration. The body weight is more than 250 mg / Kg body weight by intraperitoneal injection, and there is no problem in safety.

Hereinafter, the present invention will be described in more detail with reference to production examples of the compound represented by the formula (I), pharmacological tests, toxicity tests, and formulation examples.

Production Example 1 5.00 g (40 mmol) of pyrogallol and 600 ml of 5% sodium borate aqueous solution were taken, and dimethylsulfate 1 was added with stirring.
9 ml and 15 ml of a 15% aqueous sodium hydroxide solution are slowly added dropwise and left overnight. The reaction mixture is acidified with Congo red with 10% sulfuric acid and then extracted with 600 ml of ether. The ether solution is washed with water and then dried over anhydrous magnesium sulfate.

Crude 3-methoxycatechol obtained by distilling off the solvent
4.1 g, anhydrous potassium carbonate 8.0 g, methylene bromide 6.0 g and N, N
-Take 50 ml of dimethylformamide and continue heating under nitrogen atmosphere with stirring at around 100 ° C. for 4 hours. The reaction solution is concentrated, 100 ml of water is added, and the mixture is extracted with 200 ml of benzene. The benzene solution is washed with water and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was distilled under reduced pressure to obtain 1.56 g (25.9% yield) of 4-methoxy-1,3-benzodioxole as colorless crystals.

Production Example 2 2.51 g (18 mmol) of sesamol, 3.88 g of methyl iodide
(27 mmol), anhydrous potassium carbonate 2.5 g and acetone 35
Heat the ml with stirring at around 60 ° C for 14 hours. After cooling,
50 ml of water is added to the reaction solution, and the mixture is extracted with 150 ml of ether. The ether solution is washed successively with a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was distilled under reduced pressure to give 1.90 g (69.0% yield) of 5-methoxy-1,3-benzodioxole as colorless oil.
Get.

By using 5.02 g (27 mmol) of n-butyl iodide instead of methyl iodide in the above Production Example, 5- (n
-Butoxy) -1,3-benzodioxole 2.87 g (81.6%
Yield).

Production Example 3 After heating 3,4- (methylenedioxy) aniline 5.48 g (40 mmol) and concentrated hydrochloric acid 10 ml at about 70 ° C. with stirring, about 10 g of crushed ice was added and cooled to about 0 ° C., then sodium nitrite 2.9
10 ml of 0 g of a cold aqueous solution is added dropwise with stirring at a reaction temperature of 4 ° C. or lower, and the mixture is stirred for 30 minutes as it is. The reaction mixture is neutralized with a cold saturated aqueous solution of sodium acetate and then filtered, and the filtrate is kept at 4 ° C or lower. A solution prepared by dissolving 5.0 g of sodium hydroxide and 22.4 g of a 15% sodium methylmercaptan aqueous solution in 80 ml of water is maintained at about 75 ° C, and the above filtrate is slowly added dropwise while stirring.
After the completion of dropping, heat at about 90 ° C for 1 hour. After cooling, it is extracted with 450 ml of benzene, washed with water, and the benzene solution is dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give 1.82 g of 5-methylthio-1,3-benzodioxole as a pale yellow oil.
(27.1% yield).

Production Example 4 2,3- (Methylenedioxy) benzaldehyde 12.0 g
(80 mmol) and 300 ml of water are taken, kept at about 80 ° C., and 350 ml of an aqueous solution of 18.6 g of potassium permanganate is added dropwise over about 45 minutes while stirring. After dropping, the mixture is further stirred for 1 hour and 30 minutes, made alkaline with a 10% aqueous potassium hydroxide solution, and filtered while hot. After cooling the filtrate, acidify Congo red with dilute hydrochloric acid. The precipitated crystals are collected by filtration and dried to give crude 2,3-
6.1 g of (methylenedioxy) benzoic acid are obtained. This product and 100 ml of benzene were stirred and cooled with cold water.
2.8 g and 2 drops of pyridine are successively added dropwise, the mixture is further heated under reflux for 1 hour and 30 minutes, the solvent is distilled off, and the residue is slowly added to 28% aqueous ammonia while stirring. After keeping the liquid temperature at 15 ° C. or lower and stirring for 1 hour, the reaction liquid was filtered and the precipitated crystals were collected by filtration to obtain 5.3 g of crude 2,3- (methylenedioxy) benzamide.

Next, 4.9 g of sodium hydroxide and 50 ml of water were taken, 6.2 g of bromine was slowly added with stirring under cooling with ice-salt, and then the liquid temperature was kept at around 0 ° C., and the above 2,3- (methylene After adding 5.3 g of dioxy) benzamide and stirring for 25 minutes, the liquid temperature is further heated at around 75 ° C. for 2 hours and 30 minutes. The reaction is cooled and extracted with 300 ml ether. After washing the ether solution with water,
Dry over anhydrous magnesium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography to give 2,3- (methylenedioxy) aniline as a light brown oil.
1.90 g (17.3% overall yield) are obtained.

Production Example 5 5.20 g (38 mmol) of 3,4- (methylenedioxy) aniline, 2.2 g of sodium hydride and 50 ml of dried tetravidrofuran were heated at about 50 ° C. under a nitrogen atmosphere, and 10.8 g of dimethyl sulfate was slowly added. And then heated to reflux for 2 hours. After cooling, the mixture was stirred at room temperature for about 15 hours and then cooled to around 5 ° C, and 5 ml of methyl alcohol and 3.6 g of sodium hydroxide were added to water 8
An aqueous solution dissolved in 0 ml is slowly added dropwise with stirring, and after completion of the addition, the mixture is extracted with 150 ml of ether. The ether solution is washed with water and then dried over anhydrous potassium carbonate. After distilling off the solvent, the residue was purified by silica gel column chromatography to give 1.10 g (17.6% yield) of 5-dimethylamino-1,3-benzodioxole as a slightly reddish brown oil.
Get.

Production Example 6 5.00 g (36 mmol) of 3,4- (methylenedioxy) aniline and 10 ml of glacial acetic acid are taken, and 15 ml of acetic anhydride is added. Let stand at room temperature for 10 minutes, then keep at about 50 ° C for another 10 minutes. After cooling, the reaction solution is poured into 100 ml of cold water to precipitate crystals and then filtered. The obtained crystals were recrystallized from ethanol to give slightly brown crystals of 5-acetylamino-1,3-benzodioxole.
5.11 g (78.4% yield) are obtained.

Production Example 7 Sodium hydride (0.29 g) and dried xylene (10 ml) were added to 100
50 ml of dried xylene heated to around ℃ and dried with 2.00 g (11 mmol) of 5-acetylamino-1,3-benzodioxole
The solution dissolved in 1 is slowly added dropwise with stirring under a nitrogen atmosphere and heated at around 140 ° C for 24 hours. Then, 6.30 g of methyl iodide was added dropwise to this reaction solution with stirring, and the temperature was raised to 140 ° C.
Continue heating for an additional 8 hours. After cooling, the reaction solution was filtered, and the obtained crystals were recrystallized from ethanol to give 5-
1.21 g (56.4% yield) of (N-acetyl-N-methyl) amino-1,3-benzodioxole are obtained.

Production Example 8 3,4- (Methylenedioxy) aniline 2.50 g (18 mmol), triethylamine 2.8 g and dry tetrahydrofuran 10 ml were taken and kept at a liquid temperature of 10 ° C. or lower with stirring, and 2.30 g of methanesulfonyl chloride was slowly added dropwise. After the dropping, the stirring is continued for another 2 hours. The reaction mixture is added to a mixture of 30 ml of 2N hydrochloric acid and 30 g of ice, and then extracted with 300 ml of benzene.
The benzene solution is washed with water and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to give 1.97 g of colorless crystals of 5- (methanesulfonyl) amino-1,3-benzodioxole.
(50.3% yield).

Production Example 9 5.00 g (36 mmol) of 3,4- (methylenedioxy) aniline, 17 ml of glacial acetic acid and 35 ml of water were taken to make a uniform solution at 35 ° C., and 40 ml of an aqueous solution of 4.70 g of sodium cyanate was slowly added dropwise with stirring. After that, stirring is continued for another 2 hours at room temperature, 15 ml of water is added, and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized from 50% ethanol to give slightly brown crystals of 3,
4-Methylenedioxyphenylurea 4.30 g (65.6% yield)
Get.

Production Example 10 Pyrogallol 50.0 g (0.40 mol), acetic anhydride 38 ml, activated Amberlite IR-120B (ion exchange resin) 2
Heat 2.5 g to reflux with stirring for 5 hours. After cooling, acetone 1 was added to the reaction solution and filtered, the filtrate was concentrated, and the residue was recrystallized from benzene to obtain 35.5 g (53.3% yield) of yellow crystalline galoacetophenone.

35.5 g (0.21 mol) of the above-mentioned galoacetophenone, 60 g of anhydrous potassium carbonate and 260 ml of N, N-dimethylformamide are taken, 47.0 g of methylene bromide is added under a nitrogen atmosphere, and the mixture is heated at 105 ° C. for 5 hours while stirring. After cooling, the reaction solution is poured into 400 ml of water, and the solution is made weakly acidic with hydrochloric acid. Extraction was performed with ether 1.5, the ether solution was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography to give 2-hydroxy-3, a slightly yellow crystal. 7.63 g (20.1% yield) of 4- (methylenedioxy) acetophenone are obtained.

While stirring 7.53 g (42 mmol) of 2-bidroxy-3,4- (methylenedioxy) acetophenone and 150 ml of 2% sodium hydroxide solution under water cooling, 7.5% hydrogen peroxide solution was added.
Slowly add 33.5 ml and stir for another 10 minutes after the end of the addition. After adding concentrated hydrochloric acid to the reaction solution to make it acidic, 200 ml of water
Is added and extracted with 900 ml of ether. The ether solution is washed with saturated saline and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain 4.18 g (64.1% yield) of light brown crystals of 1,3-benzodioxole-4,5-diol. When the above-mentioned galoacetophenone was used in the same manner as above for the methyleneation reaction, colorless crystals of benzo [1,2-d; 3,4-d '] bis [1,3] dioxole 3.4
0 g (75.5% yield; total yield 5.18%) is obtained.

Production Example 11 1,3-benzodioxole 4.01 g (33 mmol), propionic anhydride 6.41 g and a catalytic amount of 70% perchloric acid were stirred at room temperature for 90 minutes, and then the reaction solution was poured into 50 ml of water. ,ether
Extract with 150 ml. The ether solution is washed successively with a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to give colorless needle crystals of 5-propionyl-1,3-benzodioxole (1.56 g (2
6.7% yield).

Instead of 1,3-benzodioxole in the above Production Example,
Benzo [1,2-d; 3,4-d '] bis [1,3] dioxole
Using 5.61 g (34 mmol) gives 4.19 g (56.0% yield) of 4-propionylbenzo [1,2-d; 3,4-d '] bis [1,3] dioxole.

Production Example 12 4-Acetylbenzo [1,2-d; 3 obtained from benzo [1,2-d; 3,4-d '] bis [1,3] dioxole and acetic anhydride according to Production Example 11 While stirring 38.5 g (185 mmol) of 2,4-d ′] bis [1,3] dioxole and 280 ml of 85% formic acid under water cooling, 100 ml of 85% formic acid and 26 g of 30% hydrogen peroxide were added.
The mixture of (1) was slowly added dropwise, the mixture was stirred for another 24 hours, and then the reaction mixture was added to ice water. The precipitated crystals are collected by filtration, hydrolyzed with 5% aqueous sodium hydroxide solution, and then concentrated with concentrated hydrochloric acid to adjust the pH.
The crude benzo [1,2-d; 3,4-d '] bis [1,3] dioxole-4-
Get all 13.5g. Benzo [1,2-d; 3,4-d '] bis [1,3] dioxol-4-ol 13.5 g (74 mmol), benzyl chloride 10.3 g, anhydrous potassium carbonate 11.3 g and
74 ml of N, N-dimethylformamide are heated with stirring at around 100 ° C. for 2 hours. After cooling, the reaction solution is filtered and the filtrate is concentrated under reduced pressure. 100 ml of water was added to the residue, and 300 ml of ether was added.
Extract with. The ether solution is washed successively with a 1N aqueous sodium hydroxide solution and water and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from methanol to give 4- (benzyloxy) benzo [1,2-d; 3,4-d '] bis [1,3] dioxole as colorless needles. 17.8g
(88.2% yield).

Subsequently, while stirring 14.2 g of N-methylformanilide and 16.1 g of phosphorus oxychloride for 1 hour at 0 ° C., the above 4-
17.8 g (65 mmol) of (benzyloxy) benzo [1,2-d; 3,4-d '] bis [1,3] dioxole is slowly added dropwise. After completion of dropping, the mixture is heated with stirring at 40 ° C for 10 hours, further heated to 70 ° C, and then the reaction solution is poured into ice. The precipitated crystals were collected by filtration, washed with water, and recrystallized from isopropanol to give 5- (benzyloxy) benzo [1,2-d; 3,4-d '] bis [1,3] dioxole as pale yellow crystals. -4-
Obtained 17.9 g of carbaldehyde (91.3% yield).

The above 5- (benzyloxy) benzo [1,2-d; 3,4-
d '] bis [1,3] dioxole-4-carbaldehyde 1
Similarly to the above, 7.9 g was treated with formic acid and hydrogen peroxide solution, and then hydrolyzed to give 5- (benzyloxy) benzo [1,2-
d; 3,4-d '] bis [1,3] dioxol-4-ol 8.
Take 90 g (31 mmol), 150 ml of methanol, 1 g of 10% palladium on carbon, and under vigorous stirring under a hydrogen atmosphere at 60 ° C.
Continue heating for 10 hours in the vicinity. After cooling, the reaction solution was filtered, the solvent was distilled off, and the residue was recrystallized from toluene to give colorless needle crystals of benzo [1,2-d; 3,4-d '] bis [1,3 ]
5.65 g (92.6% yield) of dioxole-4,5-diol are obtained.

3.64 g (43 mmol) of methylene chloride, N, N, N ', N',
Take 80 ml of N ″, N ″ -hexamethylphosphoric triamide and heat to 125 ° C. with stirring under nitrogen atmosphere.
5.65 g (29 mmol) of the above benzo [1,2-d; 3,4-d '] bis [1,3] dioxole-4,5-diol and 2.5 g of sodium hydroxide were added little by little to the solution, and Continue heating at around 125 ° C for 20 minutes. After cooling, the reaction solution is poured into ice water 1. The precipitated crystals were collected by filtration and recrystallized from toluene to give colorless crystals of benzotris [1,3] dioxole 4.9
7 g (83.0% yield) are obtained.

Production Example 13 5-Propyl-1,3-benzodiocysole 6.30 g (38 mmol) easily obtained by reduction of safrole and 30 ml of glacial acetic acid were cooled and stirred while slowly adding a mixed solution of 10.2 g of nitric acid and 10 ml of glacial acetic acid. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour after completion of the dropping, 50 ml of water is poured into the reaction solution, and 200 ml of benzene is extracted. The benzene solution is washed successively with a 5% aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium nitrate. After the solvent was distilled off, the residue was recrystallized from petroleum ether to obtain 4.80 g (59.9% yield) of yellow crystalline 5-nitro-6-propyl-1,3-benzodioxole.

While stirring 5-nitro-6-propyl-1,3-benzodioxole 4.80 g (23 mmol), reduced iron powder 5.4 g and 95% ethanol 30 ml, 18% hydrochloric acid 2.6 ml was added dropwise, and the temperature was increased to about 95 ° C. Heat for 3 hours. After cooling, the reaction solution is suction filtered, 200 ml of water is added to the filtrate, the pH is adjusted to 2 with 10% hydrochloric acid, and the mixture is washed with 300 ml of ether. The aqueous solution is adjusted to pH 11 with 10% aqueous sodium hydroxide solution and extracted with 400 ml of ether. After washing the ether solution with a saturated aqueous solution of sodium chloride,
Dry over anhydrous magnesium sulfate. After distilling off the solvent,
The residue is purified by silica gel column chromatography to obtain 2.30 g (56.0% yield; total yield 33.5%) of red oily 2-propyl-4,5- (methylenedioxy) aniline.

By using 5.78 g (38 mmol) of 5-methoxy-1,3-benzodioxole instead of 5-propyl-1,3-benzodioxole in the above Production Example, 2-methoxy-4, 3.51 g of 5- (methylenedioxy) aniline (total yield 55.3%) is obtained.

Production Example 14 2.30 g (10 mmol) of 4-propionylbenzo [1,2-d; 3,4-d '] bis [1,3] dioxole was dissolved in 11.4 g of trifluoroacetic acid, and triethylsilane was added with stirring.
2.66 g is slowly added dropwise and stirring is continued for another hour.
The reaction solution is poured into 100 ml of water and extracted with 150 ml of ether. The ether solution is washed successively with a 2% aqueous sodium hydroxide solution and water and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give 4-propylbenzo [1,2-
d; 3,4-d '] bis [1,3] dioxole 1.44 g (67.1%
Yield).

4-propionylbenzo [1,2-d; 3,4 in the above Production Example
Production Example 11 instead of -d '] bis [1,3] dioxole
By using 2.08 g (10 mmol) of 5-methoxy-6-propionyl-1,3-benzodioxole obtained from 5-methoxy-1,3-benzodioxole and propionic anhydride according to 1.22 g (62.9% yield) of 5-methoxy-6-propyl-1,3-benzodioxole are obtained.

Pharmacological test Efficacy as a liver disease therapeutic agent is usually determined by administering a test substance and a hepatic disorder-inducing substance to a test animal and examining the hepatic disorder suppressing action. Although carbon tetrachloride, chloroform, thioacetamide, D-galactosamine and the like are known as hepatopathy-inducing substances, in this test, tetrachloride which is the most widely used to make a pathological model of liver damage. Carbon was used. In addition, the inhibitory effect on liver damage of the test substance was searched using, as an index, serum glutamate / oxaloacetic transaminase (GOT) activity, which increases due to degeneration / necrosis of hepatocytes. When liver damage is caused by carbon tetrachloride, degeneration and necrosis of hepatocytes cause deviation of cell components, and GOT activity in serum is markedly increased. This method of measuring GOT activity in serum is the most suitable for knowing its inhibitory effect on frost damage by sucrose. The animals used in the test were ICR male mice, and 5 mice were used per group. Buy 4 weeks old, weighing 18-22g, and give solid feed (MF, Oriental Yeast Co., Ltd.) and water freely in a constant temperature and humidity (23 ± 1 ℃, 55 ± 5%) breeding room. The animals were preliminarily bred for one week, and those having good growth were selected and used for the test. After fasting the test animals for 19 hours in advance, the test substance was orally administered or intraperitoneally injected, and 30 minutes later, mixed with olive oil to give 0.15 v / v% carbon tetrachloride solution at 10 ml / kg body weight (carbon tetrachloride). As 0.015 ml / kg body weight)
Was injected intraperitoneally. Then, 24 hours later, blood was collected from the abdominal aorta, and then serum was separated by centrifugation (3000 rpm.10 minutes), and its GOT activity was measured. The test substance is 5%
It was suspended in an aqueous solution of gum arabic and administered at 10 ml / kg body weight for both oral administration and intraperitoneal injection. GOT activity in serum was measured by the enzyme method of Lippi et al. [Clinica.
Clinica Chimica Acta., 28, 431
-Page 437 (1970)], and the results are shown in Tables 1 and 2.

As is clear from the above pharmacological tests, the compound of the present invention has a prominent serum GOT activity resulting from degeneration / necrosis of hepatocytes due to carbon tetrachloride at a dose of 6.25 mg / Kg body weight or more in both oral administration and intraperitoneal administration. , And showed a clear inhibitory effect on liver damage.

Toxicity test The animals used in the test were ICR male mice, and 8 mice were used per group. Buy 4 weeks old, weighing 18-22g, and give solid feed (MF, Oriental Yeast Co., Ltd.) and water freely in a constant temperature and humidity (23 ± 1 ℃, 55 ± 5%) breeding room. The animals were preliminarily bred for one week, and those having good growth were selected and used for the test. Test animals were fasted for 16 hours in advance and then orally or intraperitoneally injected with the test substance. The test substance was suspended in a 5% aqueous solution of gum arabic and administered at 10 mg / kg body weight in both oral administration and intraperitoneal injection. The 50% lethal dose was calculated from the mortality rate 336 hours after administration by the Van der Waerden method [Yoshio Ban: Pharmaceutical Research Method, pp. 101-102, Asakura Shoten (1970)]. The results are shown in Table 3.

As is clear from the above toxicity test, the acute toxicity value (50% lethal dose) of the compound of the present invention is 500 mg / Kg body weight or more for oral administration and 250 mg / Kg body weight or more for intraperitoneal injection. It can withstand.

Formulation Example 1 Powder A powder is prepared by uniformly mixing 5 parts by weight of the compound of the present invention with 95 parts of lactose.

Formulation Example 2 Granules 5 parts by weight of the compound of the present invention are mixed with 93 parts of lactose, and 2 parts of hydroxypropylcellulose are used as a binder to prepare granules according to a conventional method.

Formulation Example 3 Tablets 5 parts by weight of the compound of the present invention was mixed with 91 parts of lactose, 2 parts of hydroxypropylcellulose was used as a binder to form granules according to a conventional method, and then 1 part of talc and 1 part of stearic acid. Magnesium is added and compression molding is performed to obtain tablets.

Formulation Example 4 Capsules 5 parts by weight of the compound of the present invention is mixed with 93 parts of lactose, 2 parts of hydroxypropyl cellulose is used as a binder to form granules according to a conventional method, and the resulting mixture is filled into hard gelatin capsules.

Formulation Example 5 Injection 1 part by weight of the compound of the present invention is heated and mixed with 2.5 parts of polyoxyethylene hydrogenated castor oil and 96.5 parts of physiological saline, followed by sterilization to obtain an injection.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 493/14 C07D 493/14 (72) Inventor Hiroshi Nakagawa 370 Mita-cho, Kishiwada-shi Shin Nihon Pharmaceutical Stock Association Corporate Technology Headquarters (72) Inventor Kazuo Matsumoto 370 Mita-cho, Kishiwada City Shin-Nippon Pharmaceutical Co., Ltd.Technical Headquarters (72) Inventor Hirase 370 Mita-cho, Kishiwada City Shin-Nihon Pharmaceutical Co., Ltd.

Claims (1)

(57) [Claims] 1. Formula (I): [In the formula, X is independently a lower alkoxy group, a lower alkylthio group, a lower alkanoyl group, an amino group, a lower alkylamino group, a di (lower alkyl) amino group, a lower alkanoylamino group, (N-lower alkyl-N- A lower alkanoyl) amino group, a lower alkylsulfonylamino group, or a ureido group, or two X's may be combined to form a methylenedioxy group, and Y is independently a lower alkyl group. Where n is an integer of 1 to 4 and n ′ is an integer of 0 to 3. However, the sum of n and n ′ does not exceed 4.] A therapeutic agent for liver diseases, which comprises the compound represented by